dabrafenib trametinib primelines

Dabrafenib and Trametinib, Effective Combination for BRAF-Mutated Anaplastic Thyroid Cancer

The combination of a BRAF inhibitor with a MEK inhibitor is a standard of care in patients with metastatic melanoma and non-small cell lung cancer harboring BRAF V600E mutations. These mutations occur in between 20% to 50% of patients with anaplastic thyroid cancer, a rare malignancy considered to be one of the most lethal of all cancers. Despite multimodality treatment including surgery, radiotherapy, and chemotherapy, outcomes remain dismal, with 1-year overall survival (OS) of 20% to 40%. Response rates to standard therapies are below 15%. There is an urgent need for development of better treatment strategies for this aggressive form of thyroid cancer.

In a cohort of an open-label, phase II trial, the combination of the BRAF inhibitor dabrafenib 150 mg twice daily and the MEK inhibitor trametinib 2 mg once daily was evaluated in 16 patients with locally advanced or metastatic BRAF V600E-mutated anaplastic thyroid cancer. Patients (median age of 72 years) were previously treated with surgery (88%), external beam radiotherapy (81%), and chemotherapy (38%).

At a median follow-up of 47 weeks, the overall response rate confirmed by independent radiologic review with dabrafenib plus trametinib was 69%, and 7 of 11 responses were still ongoing at the time of data cutoff. Median duration of response, progression-free survival (PFS), and OS were not reached. However, estimated 12-month PFS was 79%, and 12-month OS was 80%.

Safety was evaluated in the larger trial population of 100 patients with rare tumor histologies treated with dabrafenib and trametinib. The safety profile was consistent with that observed for this combination in melanoma. The most common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%).

The investigators concluded that dabrafenib plus trametinib combination is safe and shows robust clinical activity in advanced BRAF V600E-mutated anaplastic thyroid cancer. They highlighted that this is the first systemic regimen to demonstrate clinically meaningful benefit in this patient population and that these results support mutation testing and consideration of BRAF/MEK-targeted therapy for BRAF-mutated patients.